Orosomucoid 2 upregulation mediates liver injury-induced colorectal cancer liver metastasis by promoting EMT and cell migration

The relationship between drug-induced liver injury and liver metastasis of colorectal cancer and the underlying mechanisms are not well understood. In this study, we used carbon tetrachloride to construct a classic mouse liver injury model and injected CT26 colorectal cancer cells into the mouse spleen to simulate the natural route of colorectal cancer liver metastasis. Liver injury significantly increased the number of colorectal cancer liver metastases. Transcriptome sequencing and data-independent acquisition protein quantification identified proteins that were significantly differentially expressed in injured livers, and orosomucoid (ORM) 2 was identified as a target protein for tumor liver metastasis. In vitro experiments showed that exogenous ORM2 protein increased the expression of EMT markers such as Twist, Zeb1, Vim, Snail1 and Snail2 and chemokine ligands to promote CT26 cell migration. In addition, liver-specific overexpression of the ORM2 protein in the mouse model significantly promoted tumor cell liver metastasis without inducing liver injury. Our results indicate that drug-induced liver injury can promote colorectal cancer liver metastasis and that ORM2 can promote cell migration by inducing EMT in tumor cells. We found that DILI promotes liver metastasis of colorectal cancer in a classic DILI mouse model. Further analysis using high-throughput transcriptome sequencing and proteomics identified ORM2 as a key gene that promotes liver metastasis. ORM2 upregulation enhances tumor cell migration by promoting EMT of tumor cells and increasing the expression of chemokine ligands. Targeting ORM2 may be an effective therapeutic strategy for inhibiting malignant tumor metastasis.image